Genetic Marker Found For a Heart Disorder That Kills the Young

By NATALIE ANGIER

Published: May 14, 1991

SCIENTISTS have linked a gene to an inherited heart disorder that kills young and otherwise robust people without warning.

Particularly provocative to researchers is that the gene has already been implicated in many types of cancer, suggesting a plausible if still unproved relationship between chaos in the workings of heart muscle and the entropy of cell growth that is the hallmark of cancer.

But scientists said the most immediate importance of the result was that it provided researchers with their first genetic marker to identify people born with the virulent heart disorder, a type of cardiac arrhythmia called long QT syndrome. Right now the only way to diagnose the syndrome is through an electrocardiogram, which often gives equivocal results and is too expensive and difficult to administer on a large scale.

Using the genetic marker, doctors hope to be able to detect carriers of the disease before they have their first attack of cardiac arrhythmia, when one chamber of the heart suddenly starts pounding wildly at up to 300 beats per minute, an event that can be fatal. Those found to have inherited the heart disorder could be put on medication like beta blockers, which can prevent arrhythmia.

"What we'd like to be able to do is to look at somebody early in infancy or childhood and say, this kid has long QT syndrome," said Dr. Mark Keating at the University of Utah Health Sciences Center in Salt Lake City, the lead author of the new report, which appeared in a recent issue of the journal Science. "Because as it stands now, the first symptom of the disease often is sudden death."

The new marker has already been used to screen relatives of patients known to have the hereditary disorder, and some of those family members have been shown to harbor the genetic defect. Dr. Keating believes that the latest research will eventually yield a simple technique for screening the general population, much as newborns in the United States are now routinely tested for inherited enzyme deficiencies.

By studying a gene linked to the relatively rare hereditary syndrome, researchers may also learn something about all types of cardiac arrhythmias, which together kill about 500,000 Americans a year and yet remain among the most mysterious of medical disorders. President Bush recently suffered from arrhythmia, but his was caused by thyroid disease and had nothing to do with long QT syndrome. 1 in 10,000 Affected

Cardiologists and other specialists expressed unusually strong praise for the result.

"This is fabulous work, a major breakthrough," said Dr. Arthur J. Moss, professor of medicine at the University of Rochester School of Medicine and Dentistry in New York. "Long QT is a tragic disease because it occurs in otherwise healthy people and has a propensity to cause abrupt death. I can't tell you how many mothers I've had to counsel who have lost children to it. Preventive therapy is available, and this gene localization should permit easy identification."

Dr. Moss and his colleagues have been keeping a registry of patients with the syndrome, yet they still can only guess at the prevalence of the disorder, estimating it to affect about one in 10,000 people. The syndrome is named after the pattern sometimes seen in the electrocardiograms of afflicted patients.

Attacks of cardiac arrhythmia can be relatively mild, causing temporary lightheadedness or a fainting spell, or so severe that death follows in about eight minutes. An episode is often brought on by an event that is physically or emotionally stressful, like diving into a pool, getting into a fight or even hearing an alarm clock.

"One of the children in my paper died at the age of 10 in front of his class, when his teacher was scolding him," said Dr. Keating.

Stress releases a flood of adrenaline-like hormones into the bloodstream, he said, which somehow disrupts the electric pacemaker in charge of regulating the heartbeat. As one side of the heart starts throbbing madly, it fails to pump blood throughout the body, depriving the brain and other organs of oxygen.

The researchers found the gene linked to the disorder by studying the genealogy of a large Mormon family known to have long QT syndrome. The family had excellent records of relatives dating back to the two original brothers who immigrated to Utah from Denmark in 1850 and who each were prevented from being able to earn a living as fishermen because they had the heart syndrome. Tracing Family History

The scientists then combed through the DNA of living family members in search of telltale genetic fingerprints found on the chromosomes of those who indisputably had the heart defect, but not on the chromosomes of those who, from stringent electrocardiogram testing, almost certainly did not. That search led them to a gene on the short arm of chromosome 11, out of the 23 pairs of chromosomes sequestered in all human cells.

The position of the gene turned out to be extremely close to that of another, quite famous gene, called the ras gene, long known to foster cancerous growth in many organs when it becomes mutated by carcinogens, radiation or similar molecular insult. In fact, the heart defect gene and the cancer gene were such close chromosomal neighbors that scientists proposed they could be one and the same gene.

Dr. Keating said there was a rational reason a gene that elsewhere in the body contributed to cancer might, in heart cells, cause cardiac arrhythmia. Researchers believe that the biochemical defect underlying long QT syndrome is a problem with tiny channels in the membranes of heart cells that control the flow of potassium ions into and out of the cells. Other scientists have recently discovered that, in heart cells, the normal job of the healthy ras gene is to somehow communicate with potassium channels. Theoretically, then, some types of mutations in the ras gene could result in cardiac arrhythmia.

"It's sort of fun to think about how a gene that causes cancer could also cause cardiac arrhythmia," said Dr. Keating. "But it is not proved by any stretch of the imagination. It could be wrong."

Dr. Robert A. Weinberg of the Whitehead Institute for Biomedical Research in Cambridge, Mass., a pioneer in the study of the ras gene, said the new gene almost surely was not the cancer gene. "I think it's lying very near by, maybe one or two genes away, but to link it with cancer is inappropriate at this point," he said.

Nevertheless, scientists said that having any sort of genetic marker for the syndrome would be an immediate boon to people who fear for their own hearts or those of their children.

Photo: Dr. Mark Keating of University of Utah Health Sciences Center was the head of the team that found a genetic marker linked to a potentially fatal heart disorder. Now, he said, the first symptom is often sudden death. (Don Grayston for The New York Times)